The invention relates to dendritic chelated complexes, to methods for producing same and to pharmaceutical compositions containing same.
Magnetic resonance imaging and nuclear medicine have become essential research tools in the life sciences field since they give noninvasive and nontraumatic access to both anatomical and functional information in varied medical fields.
One main line of current development concerns functional imaging, which constitutes in particular a basic tool in understanding the mechanisms involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or multiple sclerosis (MS).
The products used in magnetic resonance imaging are contrast agents known as magnetic contrast agents, including a marker, termed magnetic marker.
The magnetic contrast agents that currently exist are compounds in which the magnetic marker is gadolinium or manganese.
In nuclear medicine, contrast agents are called scintigraphic contrast agents and include a marker termed scintigraphic marker. The scintigraphic marker that is currently most commonly used is technetium-99m.
All these contrast agents must satisfy restrictive specifications. Thus, they must have good biocompatibility, low toxicity, high stability in the organism, be effective at a low concentration and, in addition, if possible, be specific for the organs or tissues targeted (vectorization provided by the functions grafted onto the ligand).
But, the products currently placed on the market and described in the literature, in addition to the fact that they may exhibit toxicity, in particular hepatic toxicity, have low stability in the organism and are not specific for the organs or tissues targeted.
Thus, Masato Hito et al., in their article published in Magnet. Res. Imag. 2006, 24, 625-630, describe a contrast agent which is a gadolinium chelate, in which the chelating agent is diethylenetriaminepentaacetic acid (DTPA), as having specificity for the brain.
However, this is not a real vectorization of the chelate to the brain.
This is because 4% of contrast agents injected always go to the brain. Now, in the molecule proposed by Masato Hito, the number of gadolinium atoms per molecule is three, whereas in the prior contrast agents, there is just one gadolinium atom per molecule of contrast agent. Therefore, with the molecule proposed by Masato Hito, this is in reality an increase in the concentration of gadolinium arriving in the brain, and not a real vectorization of the chelate to the brain.
Furthermore, this product exhibits liver toxicity.
Min Liu et al. have proposed, in Bioconj. chem. 2005, 16, 1126-1132, contrast agents in which the marker is technetium-99m, the chelating agent is diethylenetriaminepentaacetic acid (DTPA) and the ligand is a polyethylene glycol (PEG)-based polymer.
This product, which can be used in nuclear medicine, binds to the liver and is eliminated by the kidneys, thereby enabling imaging of the kidneys.
This product, once again, is not specific for a particular organ within the meaning of vectorization of the contrast agent.
Furthermore, in this polyethylene glycol-based polymeric approach, there is a problem of reproducibility of the synthesis of the radiopharmaceutical, and also of sufficient and known purity of the product obtained, as in any polymeric synthesis.
Jakub Rudovsky et al. in Chem. Commun., 2005, 2390-2392, have proposed a dendritic gadolinium (3+) complex of a DOTA (2,2′,2″,2′″-(1,4,7,10-tetraazacyclotetradecane-1,4,7,10-tetrayl)tetraacetic acid) analog of formula:

However, in this case, the complex is at the periphery of the dendrimer, thereby preventing functionalization of the complex itself with a vectorizing agent, all the ends of the dendrimer being occupied by the chelate.
Paula Baia et al., in Eur. J. Inorg. Chem. 2005, 2110-2119, have described diethylenetriaminepentaacetic acid bisamide glycoconjugate lanthanide (III) chelates.
These molecules are composed of a Gd3+ ion-chelating structure linked to a dendritic structure of polyamide type, onto which a vectorizing agent, which is a beta-galactosyl residue, is grafted.
The vectorization is vectorization for targeting the liver.
However, in addition to the fact that this product is specific for the liver and not for the brain, it exhibits toxicity due to the polyamide dendrimer.
Patent application US No. 2006/0165601A1 describes dendritic compounds for chelating metal cations, in particular Gd3+ cations.
In these compounds, the Gd3+-chelating agent is diethylenetriaminepentaacetic acid (DTPA) and the core of the dendritic structure is a polyol compound, the dendrites of this dendritic structure being composed of polyethylene glycol chains ending with a hydroxyl (OH) or amine (NH2) or O—(C1 to C10)alkyl group.
However, these compounds have no specificity for the brain and have no particular vascular remanence compared with the known imaging products.
Thus, among all the existing and described contrast agents, to date, the only product which has a certain “specificity” for the brain is the diethylenetriaminepentaacetic acid-derived Gd3+ ion chelate described by Masato Hito, which does not display any real vectorization to the brain and which, in addition, exhibits hepatic toxicity.
All the other contrast agents are specific for the liver or for the kidneys and can exhibit toxicity for the organism, in particular in the case of the product proposed by Paula Baia et al., due to the use of polyamide dendrimers.